Two recent papers indicate that a triphenylethylene antiestrogen, tamoxifen, is an inhibitor of retroviral replication (Laurence et al., Blood, 75(3) Feb. 1, 1990; Chailleux et al., Mol. Pharma., 44, 324-327 1993). They suggest that this effect is not mediated by estrogen receptor (ER), but rather by other protein(s) referred to as antiestrogen binding site(s) (ABS) found in microsomes. This was determined using a retrovirus, not containing an estrogen response element (ERE) in its long terminal repeat, to infect an estrogen receptor (ER) negative cell line. This suggests that tamoxifen inhibits retroviral replication through an ER-independent pathway involving ABS. Moreover, ABS-specific ligands which do not bind ER diphenylmethane comounds) were found to have similar effects as tamoxifen. The inhibitory effects were not thought to be due to inactivation of reverse transcriptase (RT) activity since the activity of commercial RT was unaffected by tamoxifen. Raloxifene is a benzothiophene compound which binds ER as well as the ABS. Using purified recombinant estrogen receptor binding domain, all antiestrogens (tamoxifen, ICI 164,384) as well as 17-B-estradiol, competed raloxifene binding. Conversely, all antiestrogens competed 17-B-estradiol binding to purified ER. Binding to ABS, however, was different. Tamoxifen was an excellent competitor of raloxifene binding to whole cell lysates (aka ABS) prepared from breast MCF-7 cells. Conversely, raloxifene only partially inhibited tamoxifen binding to ABS using whole cell MCF-7 lysates. This suggests that raloxifene bound to a subset of tamoxifen binding proteins (aka ABS). In contrast, the "pure" antiestrogen ICI 164,384, as well as 17-B-estradiol itself, did not inhibit raloxifene binding to whole cell MCF-7 Lysates, and consequently, do not bind to the ABS. Interestingly, the authors of the tamoxifen study found that ICI 164,384 had no effect on viral replication. Thus, compounds which bind ABS, like raloxifene and its analogs, might be effective at inhibiting viral replication.